View source for 8cji


==Crystal structure of human tryptophan hydroxylase 1 in complex with inhibitor KM-07-052==
<StructureSection load='8cji' size='340' side='right'caption='[[8cji]], [[Resolution|resolution]] 1.65&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8cji]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8CJI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CJI FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.65&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FE:FE+(III)+ION'>FE</scene>, <scene name='pdbligand=UWC:methyl+(2~{S})-2-azanyl-3-[[3-[[3-ethyl-2,6-bis(oxidanylidene)-8-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-ylmethyl)purin-7-yl]methyl]phenyl]carbonylamino]propanoate'>UWC</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8cji FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8cji OCA], [https://pdbe.org/8cji PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8cji RCSB], [https://www.ebi.ac.uk/pdbsum/8cji PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8cji ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/TPH1_HUMAN TPH1_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Tryptophan hydroxylases catalyze the first and rate-limiting step in the biosynthesis of serotonin, a well-known neurotransmitter that plays an important role in multiple physiological functions. A reduction of serotonin levels, especially in the brain, can cause dysregulation leading to depression or insomnia. In contrast, overproduction of peripheral serotonin is associated with symptoms like carcinoid syndrome and pulmonary arterial hypertension. Recently, we developed a class of TPH inhibitors based on xanthine-benzimidazoles, characterized by a tripartite-binding mode spanning the binding sites of the cosubstrate pterin and the substrate tryptophan and by chelation of the catalytic iron ion. Herein, we describe the structure-based development of a second generation of xanthine-imidiazopyridines and -imidazothiazoles designed to inhibit TPH1 in the periphery while preventing the interaction with TPH2 in the brain. Lead compound 32 (TPT-004) shows superior pharmacokinetic and pharmacodynamic properties as well as efficacy in preclinical models of peripheral serotonin attenuation and colorectal tumor growth.

Structure-Based Design of Xanthine-Imidazopyridines and -Imidazothiazoles as Highly Potent and In Vivo Efficacious Tryptophan Hydroxylase Inhibitors.,Specker E, Wesolowski R, Schutz A, Matthes S, Mallow K, Wasinska-Kalwa M, Winkler L, Oder A, Alenina N, Pleimes D, von Kries JP, Heinemann U, Bader M, Nazare M J Med Chem. 2023 Nov 9;66(21):14866-14896. doi: 10.1021/acs.jmedchem.3c01454. , Epub 2023 Oct 31. PMID:37905925<ref>PMID:37905925</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8cji" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Heinemann U]]
[[Category: Mallow K]]
[[Category: Nazare M]]
[[Category: Schuetz A]]
[[Category: Specker E]]